Recent
studies have highlighted the enormous potential of cell therapy
for stroke. Evidence has shown that stem cells may repair the
damaged brain by increasing vascular supply by the creation of
new blood vessels, reducing inflammation, enhancing the brain's
repair mechanisms and reducing the ongoing death of brain cells.
Clinical trials have proved stem cell therapy in stroke to be
safe and a viable form of treatment.
Below is a paper commissioned by Regenecell Pty Ltd,
to supplement the current anecdotal data on the treatment of Stroke
with peer-reviewed published data relevant to umbilical cord stem
cell therapy. For additional information, contact: info@regenecell.com
Stem Cell Therapy for Stroke
by Gabi de Bie Science Writer: B.Sc.Hons., M.Sc.
Damage and Disability caused by Stroke
At present, ischaemic stroke is the third leading cause of death
in industrialised countries. With an annual incidence of 250–400
in 100 000 inhabitants, around 1 million people suffer from a
stroke each year in the United States and in the European Union(1).
Approximately a third of cases are left with some form of permanent
impairment, making stroke the single largest cause of severe disability
in the developed world. This leads to a huge social and economic
burden.
Stroke is caused by the interruption of blood flow in a brain-supplying
artery; commonly an embolus causes an occlusion (blockage) in
the blood vessel. Ischaemic stroke (cerebral infarction) and the
even more devastating intracerebral haemorrhage, cause a disturbance
of neuronal circuitry and disruption of the blood-brain-barrier
that can lead to functional disabilities – very typically destroying
a person's ability to speak and move normally. At this time, therapy
is primarily based on the prevention of recurrent (secondary)
strokes. Rehabilitation therapy is important for maximizing functional
recovery in the early phase after stroke, but once recovery has
plateaued there is no known treatment. There are still no neuroprotective
therapies available that reduce brain damage and improve neurological
recovery once a stroke has occurred(2).
Stem cell treatment could be the major breakthrough in effecting
repair of some of the damage caused by stroke.
Cell transplantation in experimental models of stroke
Research: 2001-2008
Recent studies have highlighted the enormous potential of cell
transplantation therapy for stroke. A variety of cell types derived
from humans have been tested in experimental/rodent stroke models.
Human cells that have been used in these studies belong in three
categories: (i) neural stem cells cultured from foetal tissue;
(ii) immortalised neural cell lines; and (iii) haematopoietic/endothelial
progenitors and stromal cells isolated from bone marrow, umbilical
cord blood or peripheral blood(3).
While human embryonic stem cells offer a virtually unlimited source
of neural cells for structural repair in neurological disorders
such as stroke, there are the ethical and safety concerns.Adult
neural progenitor cells can be obtained from different tissues,
can be safely expanded in vitro, and have shown promising therapeutic
effects in several neurological disorders without causing serious
side effects(2).
The purpose of this review is to focus specifically on the prospects
of umbilical cord blood cells as stroke therapy.
Review of human umbilical cord blood
cell (HUCBC) treatments for stroke: As early as
2001, a study was conducted to assess whether an intravenous infusion
of human umbilical cord blood cells in a rodent model, could enter
the brain, survive, differentiate, and improve neurological functional
recovery at 24 hours and 7 days after stroke. The study objectives
were all achieved to a certain extent(4).
In 2005 a research team at the University of South Florida investigated
strategies to effectively treat stroke patients other than by
re-canalisation of the occluded vessels in the cerebral infarcted
area. This group also investigated strategies to extend the narrow
anticoagulant treatment window to which only a minority of patients
have timely access. The following results were published: rats
receiving human cord blood cells 24 h after stroke demonstrated
improvements in behavioural defects; the 3 hour therapeutic window
for anticoagulant treatment of stroke victims may be extended
24-72 hours post stroke with the use of umbilical cord blood cell
therapy(5).
Paradoxically, a Finnish study (2006) reported that human cord
blood cells, administered intravenously 24 h after stroke in rats,
did not improve functional sensorimotor and cognitive recovery
because of limited migration of cells(6), but that
an infusion of pure CD34+ cells following focal cerebral ischemia
demonstrated some improvement in functional outcome(7).
Recently, Kim et al(8) showed that human mesenchymal
(CD34+) stem cells transplanted intravenously (ipsi- and contralateral)
into a rat after ischaemic stroke, possessed the capacity to migrate
extensively to the infarcted area. Promising data were also recently
cited for treatment of intracerebral haemorrhage (ICH): intravenous
delivery of cord blood cells might well enhance endogenous repair
mechanisms and functional recovery after ICH(9, 10).
Current knowledge supports HUCBC
as cell transplant candidate for stroke: It goes
without saying that the ideal cell for transplantation should
meet all the criteria of safety for the receiver as well as offer
the highest therapeutic potential. Therapeutic preparations for
stroke require an adequate cell number, which raises the need
to expand the precursor cell source in vitro (cell culture).
• Cord blood is composed of many cell types including haematopoietic
and endothelial stem/progenitor cells (CD34-), mesenchymal cells
(CD34+), immature lymphocytes and monocytes. It is not clear which
of these cells are important for functional recovery after stroke.
• Umbilical cord blood cells, whether delivered intracerebrally
or intravenously, target the ischaemic border. Chemokines - induced
by injury - are thought to mediate this migration process.
• Few transplanted cells are found in the brain, even when delivered
intracerebrally. Given the controversy of whether these cells
can really become neurons, it is unlikely that they act to replace
the damaged tissue; it is more feasible that they secrete factors
that enhance inherent brain repair mechanisms(11).
Evidence(review.3) suggests
that transplanted cells may work in the following ways:
• increase vascularisation: Increased blood flow in the ischaemic
area within a few days after stroke is associated with neurological
recovery. The induction of new blood vessel formation (angiogenesis)
has been reported with transplantation of several stem cells including
those from human cord blood.
• enhance endogenous (inherent) repair mechanisms. Human cord
blood cells in the ischaemic cortex increased sprouting of nerve
fibres.
• reduce death of host cells. Several cell types elicit a neuroprotective
effect whereby, presumably by the secretion of trophic factors,
there is often reduction in lesion size and inhibition of cell
death.
• reduce inflammation. It has been reported that stem cells can
directly inhibit T-cell activation, thus inhibiting the immune
response. Intravenous injection of human umbilical cord blood
cells reduced leukocyte infiltration into the brain thereby reducing
the stroke-induced inflammatory/immune response.
Clinical Trials
Results: As a consequence of the encouraging results from experimental
studies, pre-clinical phase I and II trials, using different types
of stem cells, were tested in patients suffering from stroke (see
Table 1 below). Although some of these trials could demonstrate
neurological improvements and cell transplantations appeared to
be a safe procedure, the precise mechanisms underlying the restorative
effects of stem cells were poorly known at the time of trial(2).
Table 1. Cell-based therapies tested in pre-clinical
trials (Baciguluppi et al., 2008)
Click
here to enlarge this table
NT2/D1 cells are from a human embryonic carcinoma–derived
cell line and have the capacity to develop into diverse mature
nerve-like cells (LBS neurons; Layton BioScience Inc.) When transplanted,
these neuronal cells survived, extended processes, expressed neurotransmitters,
formed functional synapses, and integrated with the host. Safety
and feasibility of cellular repair were achieved in this setting.
Although this small study was not powered to demonstrate efficacy,
valuable data will help in the design of subsequent clinical trials(3).
Future clinical trials considerations:
It has been widely proposed that further research should focus
on the development of new cell lines; on refining clinical inclusion
criteria; on evaluating the need for immunosuppression; and an
evaluation of whether ischemic stroke may be more suited to cell
therapy than haemorrhagic stroke.
• CTX0E03, a human neural stem cell line, has
been developed (by ReNeuron Group) for the treatment of stable
ischaemic stroke. The cell line has been tested in rodent stroke
models and in normal nonhuman primates. An application for a Phase
I clinical trial, running for 24 months, has been submitted to
the US Food and Drug Administration(reported in 1).
• Human umbilical cord blood cells: The use of
HUCBC for traumatic brain injury in children has just been approved
(ClinicalTrials.gov Identifier: NCT00254722). This is the first
clinical trial using these cells for a neurological disorder(reported
in 3).
• Timing of transplantation: The brain environment
changes dramatically over time after ischaemia. The optimal time
to transplantation after a stroke will depend on the cell type
used and their mechanism of action. If a treatment strategy focuses
on neuroprotective mechanisms, acute delivery of the cells will
be critical; if the cells act to enhance repair mechanisms (e.g.
angiogenesis) then early delivery would be pertinent because these
events are most prevalent in the first 2 to 3 weeks after ischemia;
if cell survival is important, then transplanting late, after
inflammation has subsided, could be beneficial(3).
• Lesion location and size While experimental
data suggest that recovery from cortical damage may be more complex
than from striatal damage, a conclusive statement can not be made
at this point. Precise anatomic location of the lesion and its
functional implication, as well as lesion size, will be critical
determinants to define the target patient populations for transplantation
therapy clinical trials.
Conclusions
Stem cell therapy for stroke holds great promise. However, many
fundamental questions related to the optimal candidate (including
the patient age, anatomic location and size of the infarct, and
medical history), the best cell type, the number and concentration
of cells, the timing of surgery, the route and site of delivery,
and the need for immunosuppression remain to be answered. Longer-term
studies are required to determine whether the cell-enhanced recovery
is sustained. Other challenges include ensuring appropriate manufacturing,
and quality control of transplanted cells. Clearly, more research
is needed to translate cell transplantation therapy to the clinic
in a timely but safe and effective manner so that the remarkable
potential already shown for cell transplantation to aid recovery
from experimental stroke can become a reality for the patient(3).
REFERENCES
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3. Cell Transplantation Therapy for Stroke Bliss
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